α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats

Abstract

The research determined the role of α-lipoic acid (ALA) in reducing the brain manifestations of insulin resistance. The mechanism of ALA action is mainly based on its ability to “scavenge” oxygen free radicals and stimulate biosynthesis of reduced glutathione (GSH), considered the most critical brain antioxidant. Although the protective effect of ALA is widely documented in various diseases, there are still no studies assessing the influence of ALA on brain metabolism in the context of insulin resistance and type 2 diabetes. The experiment was conducted on male Wistar rats fed a high-fat diet for ten weeks with intragastric administration of ALA for four weeks. We are the first to demonstrate that ALA improves the function of enzymatic and nonenzymatic brain antioxidant systems, but the protective effects of ALA were mainly observed in the hypothalamus of insulin-resistant rats. Indeed, ALA caused a significant increase in superoxide dismutase, catalase, peroxidase, and glutathione reductase activities, as well as GSH concentration and redox potential ( ${\left[\text{GSH}\right]}^2/\left[\text{GSSG}\right]$ ) in the hypothalamus of HFD-fed rats. A consequence of antioxidant barrier enhancement by ALA is the reduction of oxidation, glycation, and nitration of brain proteins, lipids, and DNA. The protective effects of ALA result from hypothalamic activation of the transcription factor Nrf2 and inhibition of NF-κB. In the hypothalamus of insulin-resistant rats, we demonstrated reduced levels of oxidation (AOPP) and glycation (AGE) protein products, 4-hydroxynoneal, 8-isoprostanes, and 3-nitrotyrosine and, in the cerebral cortex, lower levels of 8-hydroxydeoxyguanosine and peroxynitrite. In addition, we demonstrated that ALA decreases levels of proinflammatory TNF-α but also increases the synthesis of anti-inflammatory IL-10 in the hypothalamus of insulin-resistant rats. ALA also prevents neuronal apoptosis, confirming its multidirectional effects within the brain. Interestingly, we have shown no correlation between brain and serum/plasma oxidative stress biomarkers, indicating the different nature of redox imbalance at the central and systemic levels. To summarize, ALA improves antioxidant balance and diminishes oxidative/glycative stress, protein nitrosative damage, inflammation, and apoptosis, mainly in the hypothalamus of insulin-resistant rats. Further studies are needed to determine the molecular mechanism of ALA action within the brain.